madman
Super Moderator
Abstract
The negative effects of testosterone deficiency (TD) on human health and quality of life are well demonstrated, including signs, symptoms, metabolic syndrome, obesity, and increased mortality. Recently, substantial evidence emerged, demonstrating the benefits of testosterone therapy in men with classical and ‘‘age-related’’ hypogonadism. The US Food and Drug Administration (FDA) opposes testosterone therapy in men with age-related hypogonadism but not in men with classical hypogonadism. The FDA acknowledges that TD merits treatment, but the FDA made an artificial distinction between diagnoses where T treatment is warranted and others where the underlying diagnosis is unknown, and treatment is unwarranted. The FDA labeled the unknown category as ‘‘age-related.’’ Since the FDA is unable to demonstrate that one group differs in benefits or risks from the other, there are no bases for this distinction. This action by the FDA is not based on scientific or clinical evidence. There is no evidence that the response to testosterone therapy of ‘‘age-related’’ hypogonadism occurs via different physiological or biochemical mechanisms than those historically recognized conditions. Also, there is no evidence that ‘‘age-related’’ hypogonadism responds less well to testosterone therapy than ‘‘classical’’ hypogonadism. More importantly, there is no scientific or clinical evidence to suggest that the risks of testosterone therapy in men with ‘‘age-related’’ hypogonadism are worse or different for men with ‘‘classical’’ hypogonadism. For these reasons, we disagree with the FDA's position on testosterone therapy in age-related hypogonadism.
Introduction
Hypogonadism (henceforth referred to as ‘‘testosterone deficiency’’) is a clinical syndrome characterized by low serum testosterone (T) and a host of clinical signs/symptoms.1 T deficiency (TD) occurs as a result of testicular (primary) or pituitary/hypothalamic dysfunction (secondary) and is known historically as ‘‘classical’’ TD, or as a result of unknown underlying pathologies.
Although aging alone does not necessarily cause a significant decline in T levels, 2–9 the predominant form of TD, in aging men, is mixed with primary and secondary hypogonadism components, attributed to varying pathophysiology and comorbidities.Luteinizing hormone (LH) levels can vary in older men based on decreased numbers and function of Leydig cells, decreased sensitivity of the hypothalamus–pituitary-gonadal axis to feedback inhibition, and/or decreased LH pulse amplitude despite normal pulse frequency. Decreased LH pulse amplitude may potentially be related to reductions in neuronal cell secretion of the gonadotrophic releasing hormone.10,11
‘‘Age-related’’ hypogonadism (TD) is defined as ‘‘a clinical and biochemical syndrome associated with advancing age, characterized by specific symptoms, and a deficiency in serum testosterone (T)’’.12 This syndrome, which often occurs in middle-aged and older men, is often referred to as adult-onset hypogonadism.13 This syndrome does not meet the criteria for either classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism. However, it exhibits elements of both presentations.13 It is noteworthy that the signs and symptoms of TD and the response to treatment are similar, irrespective of the underlying causes (Table 1).12It should be noted that ‘‘age-related hypogonadism’’ may be a misnomer since not all healthy men experience a decline of T, as they age.2–9
‘‘Age-related hypogonadism’’ was introduced by Nguyen and his colleagues in their perspective published in New England Journal of Medicine (NEJM)14 stating the position of the US Food and Drug Administration (FDA) on this important clinical issue. In this perspective, the authors strongly expressed concerns on ‘‘Testosterone and Age-Related Hypogonadism.’’ Henceforth, in this article, the use of ‘‘age-related hypogonadism’’ is to maintain a consistent reference to the FDA original argument against the use of T in older men.
The FDA issued a statement in March 2015 opposing the use of T therapy (TTh) in the treatment of hypogonadism attributed to aging, without a defined cause. The FDA position on ‘‘age-related’’ TD is that this condition does not merit treatment.14 We disagree with the FDA's position on this very point. Given next is a summary of the rationale as to why this condition should be treated as any other clinical condition.
On October 1, 2015, an international expert consensus panel convened to discuss the negative impact of TD on human health and quality of life and evaluated the merits of TTh in men with TD. The panel unanimously approved nine resolutions suggesting that: (1) symptoms and signs of TD occur as a result of low T and may benefit from T treatment regardless of whether there is an identified underlying etiology; (2) there is no scientific basis for any age-specific recommendations against the use of T therapy in men.
*Evidence for Benefits of T Treatment in Older Men with TD
*Does It Really Matter What Causes Low T?
Conclusions
The negative effects of TD on human health and quality of life are well demonstrated, including signs, symptoms, metabolic syndrome, obesity, and increased mortality. Substantial evidence exists demonstrating the benefits of TTh in men with ‘‘age-related’’ TD (Table 2).18–36,81–136 More importantly, the T trials demonstrated that TTh confers significant and clinically meaningful health benefits in older men with low T and this treatment is safe and effective, irrespective of etiology.18–36 In addition, the T trials provided compelling evidence that T therapy confers significant benefits in the growing population of men with obesity and/or type 2 diabetes.
We are aware that the FDA, as a regulatory agency, has enormous responsibilities toward the safety of the U.S. public. Indeed, this differs from the responsibilities of practicing physicians, which are to provide the utmost care for their patients and to relieve pain and suffering, and improve quality of life. The FDA is charged with regulating the pharmaceutical industry, but the FDA is not charged with regulating the practice of medicine. We conclude that TD is a pathophysiological condition that merits T treatment, irrespective of the underlying causes, or the historical terms to define it.
The negative effects of testosterone deficiency (TD) on human health and quality of life are well demonstrated, including signs, symptoms, metabolic syndrome, obesity, and increased mortality. Recently, substantial evidence emerged, demonstrating the benefits of testosterone therapy in men with classical and ‘‘age-related’’ hypogonadism. The US Food and Drug Administration (FDA) opposes testosterone therapy in men with age-related hypogonadism but not in men with classical hypogonadism. The FDA acknowledges that TD merits treatment, but the FDA made an artificial distinction between diagnoses where T treatment is warranted and others where the underlying diagnosis is unknown, and treatment is unwarranted. The FDA labeled the unknown category as ‘‘age-related.’’ Since the FDA is unable to demonstrate that one group differs in benefits or risks from the other, there are no bases for this distinction. This action by the FDA is not based on scientific or clinical evidence. There is no evidence that the response to testosterone therapy of ‘‘age-related’’ hypogonadism occurs via different physiological or biochemical mechanisms than those historically recognized conditions. Also, there is no evidence that ‘‘age-related’’ hypogonadism responds less well to testosterone therapy than ‘‘classical’’ hypogonadism. More importantly, there is no scientific or clinical evidence to suggest that the risks of testosterone therapy in men with ‘‘age-related’’ hypogonadism are worse or different for men with ‘‘classical’’ hypogonadism. For these reasons, we disagree with the FDA's position on testosterone therapy in age-related hypogonadism.
Introduction
Hypogonadism (henceforth referred to as ‘‘testosterone deficiency’’) is a clinical syndrome characterized by low serum testosterone (T) and a host of clinical signs/symptoms.1 T deficiency (TD) occurs as a result of testicular (primary) or pituitary/hypothalamic dysfunction (secondary) and is known historically as ‘‘classical’’ TD, or as a result of unknown underlying pathologies.
Although aging alone does not necessarily cause a significant decline in T levels, 2–9 the predominant form of TD, in aging men, is mixed with primary and secondary hypogonadism components, attributed to varying pathophysiology and comorbidities.Luteinizing hormone (LH) levels can vary in older men based on decreased numbers and function of Leydig cells, decreased sensitivity of the hypothalamus–pituitary-gonadal axis to feedback inhibition, and/or decreased LH pulse amplitude despite normal pulse frequency. Decreased LH pulse amplitude may potentially be related to reductions in neuronal cell secretion of the gonadotrophic releasing hormone.10,11
‘‘Age-related’’ hypogonadism (TD) is defined as ‘‘a clinical and biochemical syndrome associated with advancing age, characterized by specific symptoms, and a deficiency in serum testosterone (T)’’.12 This syndrome, which often occurs in middle-aged and older men, is often referred to as adult-onset hypogonadism.13 This syndrome does not meet the criteria for either classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism. However, it exhibits elements of both presentations.13 It is noteworthy that the signs and symptoms of TD and the response to treatment are similar, irrespective of the underlying causes (Table 1).12It should be noted that ‘‘age-related hypogonadism’’ may be a misnomer since not all healthy men experience a decline of T, as they age.2–9
‘‘Age-related hypogonadism’’ was introduced by Nguyen and his colleagues in their perspective published in New England Journal of Medicine (NEJM)14 stating the position of the US Food and Drug Administration (FDA) on this important clinical issue. In this perspective, the authors strongly expressed concerns on ‘‘Testosterone and Age-Related Hypogonadism.’’ Henceforth, in this article, the use of ‘‘age-related hypogonadism’’ is to maintain a consistent reference to the FDA original argument against the use of T in older men.
The FDA issued a statement in March 2015 opposing the use of T therapy (TTh) in the treatment of hypogonadism attributed to aging, without a defined cause. The FDA position on ‘‘age-related’’ TD is that this condition does not merit treatment.14 We disagree with the FDA's position on this very point. Given next is a summary of the rationale as to why this condition should be treated as any other clinical condition.
On October 1, 2015, an international expert consensus panel convened to discuss the negative impact of TD on human health and quality of life and evaluated the merits of TTh in men with TD. The panel unanimously approved nine resolutions suggesting that: (1) symptoms and signs of TD occur as a result of low T and may benefit from T treatment regardless of whether there is an identified underlying etiology; (2) there is no scientific basis for any age-specific recommendations against the use of T therapy in men.
*Evidence for Benefits of T Treatment in Older Men with TD
*Does It Really Matter What Causes Low T?
Conclusions
The negative effects of TD on human health and quality of life are well demonstrated, including signs, symptoms, metabolic syndrome, obesity, and increased mortality. Substantial evidence exists demonstrating the benefits of TTh in men with ‘‘age-related’’ TD (Table 2).18–36,81–136 More importantly, the T trials demonstrated that TTh confers significant and clinically meaningful health benefits in older men with low T and this treatment is safe and effective, irrespective of etiology.18–36 In addition, the T trials provided compelling evidence that T therapy confers significant benefits in the growing population of men with obesity and/or type 2 diabetes.
We are aware that the FDA, as a regulatory agency, has enormous responsibilities toward the safety of the U.S. public. Indeed, this differs from the responsibilities of practicing physicians, which are to provide the utmost care for their patients and to relieve pain and suffering, and improve quality of life. The FDA is charged with regulating the pharmaceutical industry, but the FDA is not charged with regulating the practice of medicine. We conclude that TD is a pathophysiological condition that merits T treatment, irrespective of the underlying causes, or the historical terms to define it.
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